This application concerns a matrix-forming and skin-adhesive, anti-evaporant gel for local treatment of skin diseases, skin infections, for both curative and prophylactic treatment of wounds and treatment of insect bites and stings, in both humans and animals. More precisely, the invention relates to a gel characterized by containing lower alkanol in a concentration of more than 90% and by containing a gelling agent, such as ethyl(hydroxyethyl)cellulose, hydroxypropylcellulose or another suitable gelling agent, and possible additives, whereby the gel can be applied to the skin efficiently, easily, and without complications.
Infectious skin diseases, viral, microbial and parasitic, are widespread. Some examples of skin diseases are viral skin infections caused by, for example, Herpes simplex virus or Varicellae Zoster virus, bacterial skin infections caused by, for example, Staphylococcus aureus, fungal infections caused by, for example, Trichophyton rubrum, for eliminating skin parasites, such as Sarcoptes scabiei var. hominis. The virus infection caused by Herpes simplex, alone occurs with approximately 100 million new cases per year, and in the western world there are 250-400 million eruptions of herpes labialis per year.
Herpes simplex is caused by herpes virus (HSV). Herpes (HSV) simplex virus occurs in two different types, type 1 and type 2. Herpes on the lips and around the mouth (Herpes labialis) is usually caused by type 1; most incidences of Herpes on and around the genitals (Herpes genitalis) are caused by type 2.
The first infection with HSV (primary infection) varies symptomatologically. Usually it occurs during childhood. An this first Infection, HSV-DNA is incorporated as a latent virus into the cells. Intermittently, virus proliferation occurs, resulting in Herpes outbreaks (these outbreaks are called secondary infections). Most Herpes outbreaks in adults are secondary, where the infection flares up due to reduced resistance, febrile diseases (e.g. Pneumonia), traumas, or the effects of cold, heat., or light.
The outbreak starts with flushing, swelling, itching, and pain in the infected area followed by necrosis and a suppurative ulceration which is the most troublesome symptom. A spontaneous healing of the wounds will occur in approximately 10 to 14 days.
The outbreak of Herpes genitalisxe2x80x94mentioned abovexe2x80x94is identical to that of Herpes labialis except for the fact that Herpes genitalis is located on and around the genitals.
The number of therapeutics for, for example, HSV skin infections is very limited, and the present antiviral chemotherapy has not convincingly been proved efficient. Furthermore, there exists a few products for advancing the healing of established HSV-wounds and inhibition of further outbreaks. However, none of these products have any convincing effect.
In U.S. Pat. No. 4,628,063 Haines et al disclose the antiviral activity of lidocaine against HSV. This activity is disclosed also by Yanagi, K., et al Arch. Virol. (1989) 10: 151-159. Haines et al is cited in U.S. Pat. No. 5,331,012 by Riddick et al, who use a lidocaine composition as an anaesthetic treatment of skin lesions, some of which may be herpectic in nature. Alcohol is used as a solvent in ""012. The results of the examples in ""012, at best, confirm the antiviral performance of lidocaine disclosed by ""063. The examples do not allow any conclusions to be drawn regarding any antiviral properties of alcohol itself.
Other examples of skin disorders for which there are currently few or no adequate remedies include insect bites and stings.
Other examples of skin disorders for which there are currently few or no adequate remedies include insect bites and stings. The stings of hymenoptera (bees, wasps and ants) contain a variety of components and are biochemically and immunologically distinct between species. Direct toxic effects are mediated by mixtures of low-molecular-weight compounds such as serotonin, histamine, and acetylcholine and several kinins. Polypeptide toxins in honeybee venom include mellitin, which damages cell membranes; mast cell-degranulating protein, which causes histamine release; apamin, a neurotoxin; and adolapin, which has inflammatory action. Enzymes in venom include hyaluronidase, which allows the spread of other venom components, and phospholipases, which may be among the major venom allergens.
Uncomplicated stings cause immediate pain, a wheal-and-flare reaction, and local edema and swelling that subside in a few hours. Multiple stings can lead to vomiting, diarrhea, generalised edema, dyspnea, hypotension, and collapse. Rhabdomyolysis and intravascular hemolysis may cause renal failure. Death from the direct effects of venom has followed 300 to 500 honeybee stings.
Large local reactions that spread xe2x89xa710 cm around the sting site over 24 to 48 hours are not uncommon. These reactions may resemble cellulitis but are caused by hypersensitivity rather than secondary infection. Such reactions tend to recur on subsequent exposure but seldom are accompanied by anaphylaxis and are not prevented by venom immunotherapy.
An estimated 0.4 to 4.0 percent of the US population exhibits clinical immediate-type hypersensitivity to insect stings, and 15 percent may have asymptomatic sensitization manifested by positive skin tests. Persons who experience severe allergic reactions are likely to have similar reactions after subsequent stings; occasionally, adults who have had mild reactions later experience serious reactions. Mild anaphylactic reactions from insect stings, as from other causes, consist of nausea, abdominal cramping, generalised urticaria, flushing and angioedema. Serious reactions, including upper airway edema, bronchospasm, hypotension, and shock, may be rapidly fatal. Severe reactions usually begin within 10 minutes of the sting and only rarely develop after 5 hours. Unusual complications, including serum sickness, vasculitis, neuritis, and encephalitis, develop several days or weeks after a sting.
From the literature it is known to use alcohol as disinfectant against, for example, virus including HSVxe2x80x94see, for example, R. Tyler; Journal of Hospital Infection (8: 22-29; 1987). The present inventors have found that when using alcohols as normal liquids (i.e. without taking steps to avoid evaporation) a poor and very brief effect is achieved due to the very rapid evaporation of the alcohols. Also the use of alcohols at concentrations below 90% by weight gives inadequate results.
Furthermore, Moldenhauer, in Zbl. Bakr. Hyg., I Abt. Orig. B 179, 544-554 (1984) compares surface disinfection properties of ethanol, isopropanol, formaldehyde and benzalkonium chloride by suspending virus suspension (including HSV, influenza, cocksackie-B and mumps) in those compounds or solutions. Alcohol concentrations above 90% were not tested. Furthermore in these two references alcohol is being used for surface disinfection properties and not for treatment of infections and the symptoms thereof.
In U.S. Pat. No. 5,145,663, a disinfectant, consisting of 65-75% isopropyl alcohol, 8-12% propylene glycol, and potential inert ingredients or disinfectants or antiseptics, is mentioned. The patent does not mention gels.
In GB-A-2017491 a gel containing alcohol is used as a hand-wash for bacterial disinfection.
In U.S. Pat. No. 5,288,486 viscosified alcohol compositions containing 30 to 90% alcohol are used to disinfect hands and sites of invasine medical procedures. The examples show antimicrobial activity and activity against the yeast Candida albicans, but not on skin infected with such microbes.
In the above references describing the use of alcohol, either as such or as a solvent for other active disinfectant agents, in surface disinfection of the skin, the alcohol will remain in contact with the skin for a relatively short period of time. The compositions, if they are washing compositions when they may contain a thickener such as sodium chloride, are generally rinsed off with water. Treatment with no-rinse compositions and alcohol wipes applies a relatively low amount of composition and the alcohol evaporates quickly. The alcohol is, in particular, not in contact with the skin long enough for penetration to layers below the stratum corneum (dermis and epidermis).
Ethanol has been used extensively in pharmaceutical compositions used for topical application to the skin. Compositions including a gelling agent have, likewise, been used for such application. However in none of these disclosures is the alcohol itself used as an agent for treating skin diseases. The following references are relevant.
In U.S. Pat. No. 3,016,328 and in U.S. Pat. No. 4,590,214 a mixture of a dialdehyde and an alcohol is mentioned. Without evaluating the effect, it can be established that none of these products include alcohol and gel-forming agents.
WO 93/00114 describes a method for reducing the duration of HSV-infection by applying a mixture of an anaesthetic and a surface-active ingredient with suitable antiviral activity. It does not mention gelling agents.
U.S. Pat. No. 4,247,547 mentions the use of gels containing alcohols and the dermatologically active tretinoin for treatment of acne. Tretinoin is a skin-irritant and the compositions would be wholly unsuitable for treatment of skin infected by HSV. Also the concentration of water in the compositions is unclear.
In Chemical Abstracts 90:76564r (1979) an antiseptic paste is disclosed containing about 80% by weight ethanol, 13% water and a thickener.
U.S. Pat. No. 5,013,545 describes a gel consisting of about 60 to about 90% ethanol, 0.5-30% water, and an active ingredient, such as an antihistamine. In the context of the disclosure, where rapid bactericidal and antiseptic performance is sought, the preferred range for the alcohol concentration is 60 to 80% values of more than 90% for the alcohol concentration are contraindicated by the cross-referenced text book by Morton, xe2x80x9cAlcoholsxe2x80x9d in Disinfection, Sterilisation and Preservation 2nd ed. (1977) pp301 et seq. Morton discloses that (ungelled) compositions containing more than 90% alcohol have bactericidal performance which is too slow for the activity sought by ""545. This patent does not mention activity on viral skin infections such as Herpes. Further, none of the worked examples teaches how to produce a stable gel with more than 80% alcohol.
U.S. Pat. No. 5,098,717 describes a gel based on 60-90% ethanol and as active ingredients an antihistamine and an antipruritic.
Carrier gels for pharmaceuticals based on ethanol and water are described in the patent literature, see, for example, SE 466134. In U.S. Pat. No. 4,593,048 it is mentioned that the penetration into the circulation by pharmaceuticals, dissolved in ethanol and applied topically, is accelerated when various adjuvants are used. The formulation contains surface-active ingredients as penetration aids for pharmaceuticals for percutaneous systematic administration. The compositions are not used to treat skin disorders.
An article by B. Rodu and F. Lakeman (xe2x80x9cIn vitro virucidal activity by component of a topical film-forming medication,xe2x80x9d J.Oral Pathology 17: 324326; 1988) mentions in vitro trials of a preparation consisting of approximately 80% ethanol, 7% tannic acid, 2.5% salicylic acid, and 1% boron acid. The tests were intended to evaluate the in vitro properties of the product Zilactin, which contains those ingredients and a hydroxy propylcellulose gelling agent. The in vivo performance of the gel against HSV has, however been found to be limited.
A specific antiviral preparation for topical treatment of Herpes is Zovir/Zovirax cream (Zovir is a registered trademark), which contains 5% aciclovir.
The United States Pharmacopeial Convention (1998) writes: Topical acyclovir is not effective in the treatment of recurrent herpes genitalia of herpes febrilis (labialis) infections in nonimmunocompromised patients, although topical acyclovir may cause some reduction in the duration of viral shedding. Also, there is no evidence that topical acyclovir will prevent the transmission of herpes infection to others or that it will prevent recurrent infections in the absence of signs and symptoms of infection. Further, (From Harrison""s Principles of Internal Medicine, 14th edition): Acyclovir-resistant strains of HSV are being identified with increasing frequency, especially in HIV-infected persons.
Acyclovir has been administered systemically for the treatment of Varicellae zoster virus. However reports have indicated that the treatment limited the immune response with consequent failure to develop resistance to the disease.
Surprisingly, it has now turned out that it is possible to produce an effective gel for treating skin diseases and for controlling skin parasites without using anti-histamines, anaesthetics, anti-inflammatory agents, and totally without using pharmaceuticals, including biocides against skin parasites.
Ethyl hydroxy ethylcellulose (EHEC) is produced by a first swelling native cellulose in alkali, then adding ethylene oxide to cellulose hydroxyl groups activated in the first step, then etherifying hydroxyl groups in the product by reacting them with ethyl chloride after alkali treatment. In the ethylene oxide treatment step ethoxy units may be added to the hydroxyl group on a pendant group derived from the earlier reaction of an ethylene oxide molecule with a cellulose-hydroxyl group. In the etherification step, hydroxyl groups of pendant groups and of cellulose-hydroxyl group may be reacted. The polymer product thus contains ethoxy 2-ethoxyethyleneoxy and ethoxypoly(ethyleneoxy) pendant groups. The reactions can be controlled so as to provide EHEC products with a variety of different degrees of substitution, and molar substitution (i.e. a measure of the average ethyleneoxy units per etherified group). These parameters, as well as the degree of polymerisation/molecular weight, affect the properties of the polymer in solution.
The performance of EHEC in aqueous systems, where it is used as a thickener and dispersing agent, for instance in paints and cement based mortar, has been studied (Txc3x6rnquist, J, Farg och Lack Scandinavia, 31, 291-295 (1985), Carlsson, A et al polymer, 27, 431-436 (1986)).
One object of the invention is to provide a new method of treatment of insect bites and stings by application to the skin at the site of the said bite or sting of a composition comprising high concentration of alkanol.
Another object of the invention is to provide a new method of treatment of skin infected by herpes virus (Herpes simplex and Herpes varicellae-zoster virus) by application, usually repeated application, of a composition in which alkanol is present in high concentration and as essentially the sole anti-viral active ingredient.
Another object of the invention is to provide a new method of treatment of intracellular herpes simplex viral infection by application to the infected tissue of a composition in which alkanol is present in high concentration and as essentially the sole antiviral active ingredient.
Another object is to provide novel compositions comprising gelled C1, C3 and/or C4 alkanols for treatment of skin disorders and the use of such compositions in methods of treating skin disorders.
A new gel-form pharmaceutical composition according to the invention comprises a liquid and a high molecular weight polymer gelling agent dissolved in the liquid, characterised in that the composition comprises more than 90% by weight based on the total weight of the composition of a lower alkanol which has up to four carbon atoms and less than 10% by weight water based on the total weight of the composition.
The composition optionally comprises one (or more) enhancing agent which enhances the effect (for instance the antiviral effect) of the alkanol composition. In one aspect of the invention, preferably the composition is substantially free of antihistamines, anaesthetics, anti-inflammatories, irritants and any immunogenic compounds or compounds which disturb the immune system. Consequently, in the invention, concentration and crystallization of medicaments (which is a potential problem with prior art compositions in which alcohol is held as a solvent vehicle for such active compounds) will not occur when the solvent evaporates. Consequently, local overdosing resulting in irritative inconveniences is totally avoided.
In the present specification it will be understood that the term akanol includes alkane-mono-ols, alkane-diols, alkane-tri-ols and other alkane-poly-ols. Two or more hydroxyl groups in a single molecule must be attached to different carbon atoms. The lower alkanol preferably contains up to 4, preferably up to 3 carbon atoms. It may be a glycol (an aliphatic diol in which the hydroxyl groups are attached to different, not necessarily adjacent, carbon atoms) or polyol but is preferably a mono hydroxy compound. It can be a mixture of such compounds. Most preferably it includes ethanol optionally in combination with other lower alkanols.
In a further aspect of the invention there is provided a novel composition comprising more than 90% by weight of an alkanol selected from isopropanol, n-propanol, mixtures of isopropanol and n-propanol, mixtures of propanol, selected from isopropanol, n-propanol and mixtures thereof, and ethanol in which the ratio of propanol to ethanol is in the range 10:1 to 1:10, a polymeric gelling agent in an amount in the range 0.1 to 10% by weight and less than 10% by weight water.
In a further aspect of the invention there is provided a novel composition comprising more than 90% by weight of an alkanol selected from C1, C3 and C4 alkanols, mixtures thereof and mixtures thereof with ethanol wherein the ratio of (C1, C3 and/or C4 alkanol): ethanol is in the range 1:10 to 10:1, a polymeric gelling agent in an amount in the range 0.1 to 10% by weight and less than 10% by weight water.
In a further aspect there is provided a novel composition comprising at least 70% by weight n-propanol, less than 30% by weight water and 0.1 to 10% by weight polymeric gelling agent.
In a further aspect there is provided a novel composition comprising at least 80% by weight of an alkanol selected from C3 and C4 alkane-mono-ols and mixtures thereof, 0.1 to 10% by weight of a polymeric gelling agent and less than 10% by weight water.
In all the above aspects it may be desirable to incorporate an effective denaturing amount of denaturant such as isopropanol or methanol as part of the alkanol mixture, where this is formed of other alkanols. Effective levels are in the range 1-10%. Other denaturants which may be included in the composition as part of non-alkanol component are diethylphthalate, e.g. in an amount of 0.1-2% by weight.
Thus, it has now surprisingly been found that a gel containing more than 90% ethanol or other lower alkanol is very effective for topical treatment of, for example, skin infections and skin parasites.
When using suitable gelling agents it is possible to transform a concentrated alkanol into a very suitable, effective, and stable gel. The invention is of particular value in the treatment of viral infections whose systems involve skin eruptions, especially herpes infections.
Thus, the preparation of the invention consists of concentrated alkanol in such a form that it is usable as a topical preparation for immediate application to the diseased area of the skin including mucous membranes. While ethanol in lower concentrations, for example in concentrations of less than 60%, gives a distinct pain reaction, the use of the concentrated alcohol, for example in concentrations of more than 90% according to the invention, is almost painless even when it is used in open wounds. The preparation has a combined effect which is utilised optimally and over a prolonged period in the invention. Thus, an effective combination of drying the edematous tissue, coagulating proteins and destroying the pathogenic/agent, is achieved, and later, when it has dried, the gelling agent acts as a plaster protecting against infection and evaporation.
The gels of the invention create a matrix formation that prevents the alcohol from leaking out of the gel and flowing away from the site where the gel has been applied. At the same time the gel is gentle to the skin and easy to apply. It is possible, and preferred, for the composition to be transparent, and for the dried film of polymer gelling agent, remaining after the composition has dried on the skin, to be transparent to allow the underlying skin to be visible throughout treatment.
When the gel has dried it forms a protective film over a wound such as an HSV outbreak. Separately, all these activities contribute to avoid secondary bacterial infection. With the evaporation-limiting matrix formation the gel forms a barrier film on the surface between gel and air by means of which the evaporation of alcohol is drastically reduced. For a long time the alcohol in this way remains in contact with the skin by which means the ethanol has a possibility of diffusing into the skin and perform its effect in depth. Further, the plaster action of the gel prevents a rapid evaporation of the alcohol diffused into the tissue and, finally, after drying the plaster effect of the gel will offer protection against reinfection of the affected area. Thus, when choosing a gelling agent or a mixture of gelling agents, which form matrix with the ethanol and that form a film on the surface of the gel against the atmosphere, the extraordinary prolonged effect of the gel is achieved according to the invention.
The content of water is important to the effectiveness. The content should be less than 10%, preferably less than 5%, and optimally, in some cases, less than 1%. The amount of water should be below the equilibrium content of the composition under ambient conditions, that is under normal storage conditions at 20-24xc2x0 C. and at 50-100% relative humidity, as well as at such humidity levels at temperatures up to body temperature (eg 37xc2x0 C.). Thus the composition as a whole should, in effect be hygroscopic. The hygroscopicity is preferably due to the concentration of alkanol being higher than the concentration of alkanol in the presence of humid air. The equilibrium concentration of water in ethanol under these conditions is in the range 3 to 7% by weight of the sum of water and ethanol. The gelling agent may also contribute some hygroscopicity. If the content of water is too high the drying and antimicrobial effect and especially the antiviral effect is reduced which means that the effectiveness of the gel is reduced. Similarly, the concentration of alkanol is crucial to the effect on external skin parasites. It seems that the high concentration of alkanol may allow the alkanol to penetrate to layers of skin below the stratum corneum in therapeutic concentrations.
One of or a combination of several gelling agents which are usually soluble in the alkanol can be used. The gelling agent is a polymer, which may be linear, branched or cross-linked and may be naturally-derived, a derivative of such polymers, or may be wholly synthetic. The molecular weight is usually high, for instance at least 104, preferably at least 5xc3x97105, and up to several million, for instance more than 106. The polymer is preferably non-ionic in the composition. Suitable gelling agents include cellulose derivatives, especially cellulose ethers, such as alkyl- and hydroxyalkyl cellulose, for instance ethylcellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, especially ethyl(hydroxyethyl) cellulose (EHEC), carboxy methyl cellulose, other polysaccharides and derivatives, such as naturally derived polysaccharides and derivatives thereof, including modified carragenan; and synthetic polymers such as polyethylene glycols, polyethylene oxides, polyvinyl pyrrolidones and poly acrylic acid.
The cellulose derivatives which are useful in the invention usually have a high molecular weight, for instance more than 106 , although polymers with molecular weight from 105 upwards may be useful. The degree of substitution/derivatisation of cellulose ether derivatives useful in the invention is preferably relatively high, for instance higher than 1.0.
Particularly suitable cellulosic gelling agent for a highly concentrated ethanol are hydroxypropylcellulose (HPC), and ethyl(hydroxyethyl)cellulose (EHEC), EHEC is a derivative of cellulose with CA registration number 9004-58-4. EHEC is, as an example, sold under the trademark BERMOCOLL from Berol Kemi AB, such as BERMOCOLL OS. For example, an effectively gelling EHEC is achieved at degree of polymerisation of approximately 3,200, a degree of substitution of approximately 1.7 for ethylene (DS-ethyl=1.7) and of approximately 1.5 for hydroxyethyl (MS-hydroxyethyl=1.5). Cellulose ethers including EHEC are more precisely described in Kirk-Othmer, xe2x80x9cEncyclopedia of Chemical Technology,xe2x80x9d 5:143,1979(3. edition). See also xe2x80x9cFaerg och Lack Scandinaviaxe2x80x9d 31:291-298;1985.
HPC is sold under the tradename KLUCEL(trademark). KLUCEL hydroxypropylcellulose is a nonionic cellulose ether with a versatile combination of properties. It combines dual solubility in aqueous and polar organic solvents, thermoplasticity, and surface activity with thickening and stabilizing properties. Pharmaceutical grades of KLUCEL that meet the specifications of the European Pharmacopeia and, respectively, National Formulary are designated EP and NF.
Acrylic acid polymerics are also particularly suitable as gelling agent. Acrylic acid polymerics are, as an example, sold under the trademark Carbopol from BF Goodrich, such as Carbopol 940 and 941, Carbopol 940 NF and 941 NF, Carbopol 980 NF and 981 NF, or Carbopol 1342 and 1382. Those Carbopols are high molecular, non-linear polymerics of acrylic acid cross-linked with polyalkenyl polyether. Acrylic acid polymerics are more precisely described in xe2x80x9cKirk-Othmer, Encyclopedia of Chem.Tech,xe2x80x9d 20:216;1982 and in Ullmanns Encyclopedia of Ind.Chem,xe2x80x9d A21:752;1992.
Polyvinylpyrrolidones are a third example of a particularly suitable gelling agent. Polyvinylpyrrolidones, as an example, are sold under the trademark PVP K-30 and PVP K-90 from GAP. Polyvinylpyrrolidones are high molecular polymerics which are described in more detail in xe2x80x9cKirk-Otmer, Encyclopedia of Chem.Tech.,xe2x80x9d 23:963;1983 and in xe2x80x9cUllmanns Encyclopedia of Ind.Chem.,xe2x80x9d A21:143;1992 and others.
The gelling agents are used in amounts between 0.1% and 10%, depending on the choice of gelling agent or mixture of gelling agents, depending on the composition, the desired texture etc. The amount should preferably be sufficient to render the composition gel-like at room temperature and at normal body temperature so that it remains in place on the skin and does not spread or run off after application. The gel-like consistency, which is due to the viscoelastic properties of polymer solutions in solvents, depends upon molecular weight, degree of substitution as well as, for derivatives such as EHEC where the several units of derivatising agent may be added to each derivatised saccharide hydroxyl group, the molar substitution and type of substituent as well as the concentrations of polymer in the composition. The compositions should generally have high viscosity under low shear but, for optimal handling during manufacture and application, should be shear thinning. This combination of features can be achieved by appropriate selection of properties, as illustrated in the accompanying examples, for instance. For example, the viscosity-increasing effect of EHEC depends on the degree of polymerization and on the degree of substitution and, for the EHEC having a degree of polymerisation of 3200, mentioned above, a suitable concentration in ethanol is 0.5 to 2.0%, for instance around 1.0%.
This, for example, applies to pH-regulating agents such as bases, eg alkaline inorganic compounds or organic bases and mixtures by which some actions of alkanols are increased under certain circumstances. Inorganic bases which may be used include sodium and potassium hydroxide and carbamate. Organic bases include triethylamine, triethanol amine and other alkanolamines. For example, a content of 0.02% NaOH will increase the antiviral action of the ethanol. Thus in one embodiment of the invention the composition has a pH in the range 6 to 9.5, preferably an alkaline pH. Other additives that can be mentioned are the substances that form part of medicinal gels such as emollients, colorants, perfumes, menthol, camphor, w-protective agents etc. and the like by which the gel can be supplemented with further functional properties.
The composition should, however, be substantially free of pharmacologically active ingredients other than these optional enhancing agents.
The composition is preferably supplied in an air and moisture/moisture vapour-impermeable container. Such containers are, for instance, squeezable tubes, especially formed of metal foils or of plastics materials having moisture barrier properties. Such containers prevent compositions, whose water content is such that the composition is hygroscopic, from absorbing moisture from the atmosphere during storage and before use. By the use of such containers, therefore loss of drying activity of the gels is minimised.
According to the invention we have not only succeeded in producing a gelxe2x80x94with a concentrated content of alkanolxe2x80x94which is very effective and suitable for treatment of skin diseases, which is skin-adhesive and gentle to the skin, and which preferably does not contain other medicaments or pharmaceuticals. The mere omission of medicaments and pharmaceuticals such as antihistamines etc. has as a consequence that no adverse reactions or side-effects occur and that allergic reactions are completely eliminated. Further to this, as a consequence of the special mechanism of activity of alkanol, absolutely no resistance can develop among the responsible microorganisms or parasites. In choosing a gel with a matrix structure it is achieved that the alkanol, after application, does not accumulate in, for example, the nasolabial fissure at the angle of the mouth or in the groin but remains where applied. Further, as the gel shows pseudoplastic (viscoelastic) properties the gel is very easy to apply, and at the same time it regains its matrix structure and its structural firmness and exactly by that, as mentioned, remains on the site of application.
Because of the high concentration of alcohol the gel possesses other surprising properties. The skin-adhesive properties turn out to be very good, partially due to, the high content of alkanol, but also because of the choice of gelling agent, where especially EHEC, HPC, ASP, and PVP or combinations of these have lipophilic and hydrophilic properties giving the alcohol a very good contact with the skin.
The gelling agents, especially EHEC, HPC, ASP, and PVP or combinations of these, have hydrophobic-hydrophilic properties by which the release of alcohol towards the skin from the slow release matrix structure of the gel is adjustable. By doing this, it can be obtained that no release-inhibiting film is created between the alcohol-gel and the skin/mucous membranes. This, of course, is important for the continuous effect of the alcohol-gel on the site of application.
Thus, it is not necessary to add surfactants to achieve the correct contact between the skin and the gel as is the case in U.S. Pat. No. 4,593,048. The composition should generally be free of added surfactants.
Similarly, it is not necessary to add special binding agents nor to use plaster or tape in order to adhere the gel to the skin.
Gels according to the invention are physically and chemically stable for at least 12 months at 50xc2x0 C. Among other things this is a result of the fact that addition of other active ingredients or adjuvants, which together with medicament or biocide may be labile during production and storage, is not needed. It is not necessary to add actual medicaments that, in turn, would require protective antioxidants etc. to secure the chemical stability of the very same medicaments during production and storage.
As the gel does not contain actual skin irritants it is, as mentioned, not necessary to add anti-irritants such as anti-histamines, anti-inflammatory agents or similar agents.
Because of the concentrated content of alcohol the gel is self-preserving. It is therefore not necessary to add antimicrobial preservatives against fungal growths nor products against bacteria or other micro-organisms, and it is not necessary to store the gel in refrigerator or the like. Omitting all these additives in the gel means that undesirable side-effects of such additives are eliminated.
Two very important properties are achieved in the invention by omitting surfactants, skin adhesives, pharmaceuticals, medicaments, antioxidants, antihistamines, or other anti-inflammatory agents, and because it is not necessary to add preservatives against fungi, bacteria, or other micro-organisms to the gel. First, in all simplicity, the gel is composed of non-allergenic substances. Secondly, owing to its special mode of action towards the infectious agents alkanol does not give rise to development of resistance. Furthermore the product does not disturb the hosts immune response.
For the sake of completeness it should be mentioned that many skin diseases, for example, Herpes simplex are complicated by secondary, usually bacterial infections. It is not necessary to add other pharmaceuticals to the gel to avoid secondary infections, as the alkanols in the gel with the long-term effect disinfects the area and protects it against reinfection via the plaster effect of the dried gel until the wound has healed.
Especially regarding Herpes infections the drying and protein coagulating effect is of great importance. The primary phases of the recurrent herpes outbreaks (secondary infections) are characterized by the formation of blisters, full of liquid. Apart from an immediate improvement of the itching and the pain reaction, a drying action on the oedema and blisters, that have already formed, is achieved when the preparation is applied at an early stage, and thus the blisters will disappear rapidly. If the herpes outbreak is not treated early enough the blisters will burst resulting in the formation of suppurating, open wounds that are characteristic of the later phases. When used during these phases, the preparation has an immediate drying effect by means of which the secretion ends, and the protein coagulating action destroy the superficial, necrotic cells.
The drying effect makes the product useful on moist skin areas. Here the drying effect has an immediate prophylactic action in relation to bacterial infections through a reduction of the growth conditions.
Similar advantages are seen when the gel is used to treat skin eruptions associated with other viral infections such as chickenpox. When applied to such skin eruptions the formation of blisters is prevented or they are dried and itching is minimised. The breaking of the skin with subsequent risk of infection is thus prevented.
In this connection we can also mention accidental skin injuries such as wounds and skin abrasions where the antimicrobial effect combined with the plaster action of the gel after drying has an indisputable preventive action in relation to wound infections.
The gel is further suitable for prophylactic treatment of physical skin injuries such as cuts, abrasions etc. This indication is not only based on the antimicrobial property of the preparation, but also on the protective effect of the dried gel having the xe2x80x9cbuilt-inxe2x80x9d plaster effect that is achieved when the preparation has dried.
It is believed that use of the preparation in connection with treatment of burns will have a useful infectious prophylactic effect. Some eczematous diseases including allergic skin diseases are characterized by secondary infections. Here the invention will have great importance too, not least because of the non-allergenic property of the composition.
As mentioned above the gel is suitable for controlling externally parasitical and troublesome organisms. For example, the gel is suitable for external treatment of scabies, chigger and other ectoparasites.
A very effective preparation against skin infections and for eliminating external skin parasites can be obtained when using a gel in which the liquid consists of concentrated ethanol or a concentrated mixture of ethanol and other short-chained alkanols such as isopropanol or propylene glycol and containing in addition, additives such as drying and disinfecting agents, as well as the gelling agent, but no other ingredients.
The gel is also found to be useful for application to the site of inset bites and stings. The effect is thought to be due at least partially to the function of the concentrated alcohol in causing toxoid proteins in the sting to coagulate and be rendered inactive.